Alzheimer's disease (AD) is a chronic inflammatory process, and the pro- inflammatory cytokines interleukin-I (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) have been implicated in its pathogenesis. Estrogen replacement therapy (ERT) has beneficial effects on the risk for and the clinical course of AD, but the exact mechanism by which ERT exerts this protective effect is unknown. Preliminary data from our laboratory and others have established that estrogen can modulate the production of IL-1, IL-6, and TNF-alpha in several cell types. Estrogen, then, may influence risk for developing AD by altering the expression of the genes for these cytokines by inflammatory cells in the CNS (glial cells). We propose to establish a cell culture model system in order to study the effect of estrogen on the production of these cytokines and on the expression of their respective genes in glial cells. We will test the specificity of any observed estrogen effect by substituting other steroids for estrogen and will attempt to block any estrogenic effect with specific estrogen receptor antagonists. These pilot studies will serve as the basis for further experiments to elucidate the molecular mechanisms of cytokine gene regulation by estrogen in neuroglia. Such information may allow the development of tissue-specific compounds to inhibit the inflammatory process in AD. To our knowledge, this is a novel approach to clarify the role of estrogen in the prevention of AD. Resultant data will need to be followed up by studies in primary cells, whole animals and humans.